High affinity binding of the peptide agonist TIP-39 to the parathyroid hormone 2 (PTH₂) receptor requires the hydroxyl group of Tyr-318 on transmembrane helix 5

TIP39 (“tuberoinfundibular peptide of 39 residues”) acts via the parathyroid hormone 2 receptor, PTH₂, a Family B G protein-coupled receptor (GPCR). Despite the importance of GPCRs in human physiology and pharmacotherapy, little is known about the molecular details of the TIP39-PTH₂ interaction. To address this, we utilised the different pharmacological profiles of TIP39 and PTH(1-34) at PTH₂ and its related receptor PTH₁: TIP39 being an agonist at the former but an antagonist at the latter, while PTH(1-34) activates both. A total of 23 site-directed mutations of PTH₂, in which residues were substituted to the equivalent in PTH₁, were made and pharmacologically screened for agonist activity. Follow-up mutations were analysed by radioligand binding and cAMP assays. A model of the TIP39-PTH₂ complex was built and analysed using molecular dynamics. Only Tyr318-Ile displayed reduced TIP39 potency, despite having increased PTH(1-34) potency, and further mutagenesis and analysis at this site demonstrated that this was due to reduced TIP39 affinity at Tyr318-Ile (pIC50 = 6.01±0.03) compared with wild type (pIC₅₀ = 7.81±0.03). The hydroxyl group of the Tyr-318’s side chain was shown to be important for TIP39 binding, with the Tyr318-Phe mutant displaying 13-fold lower affinity and 35-fold lower potency compared with wild type. TIP39 truncated by up to 5 residues at the N-terminus was still sensitive to the mutations at Tyr-318, suggesting that it interacts with a region within TIP39(6-39). Molecular modelling and molecular dynamics simulations suggest that the selectivity is based on an interaction between the Tyr-318 hydroxyl group with the carboxylate side chain of Asp-7 of the peptide

Coeducation:A Contested Practice in Nineteenth- and Twentieth-Century Secondary Schooling

This chapter discusses the history of coeducation in secondary schooling, mainly in Europe and North America. The analysis focuses on the gendered characteristics of educational systems and curricula, as well as on national discourses about single-sex or mixed schooling. The focus is on the latter half of the nineteenth and the first decades of the twentieth century, when the merits and perils of coeducation were debated for this stage of schooling. Until after World War II, children of the working class hardly ever attended school past the age of 13 or 14. Therefore, this is a history of middle- and upper-class education. In the early nineteenth century, girls had to do with a very limited, private education that prepared only for homemaking and motherhood, while boys could attend public grammar schools that opened the door to the university and the professions. From the mid-nineteenth century, initiatives to improve the quality of girls’ education were taken. Few countries opened up boys’ public schools for girls; in most cases, new girls’ schools were established with more serious but still unequal curricula, focusing mainly on humanities. Schools teaching a curriculum equivalent to that of the boys’ schools were not created until after the turn of the century, when a more critical view of coeducation became the rule. Democratization and coeducation came hand in hand with the introduction of comprehensive mixed secondary schooling in the 1960s and 1970s. The shortcomings of coeducation, however, were not rediscovered until after it had generally been introduced

Investigating the effects of external fields polarization on the coupling of pure magnetic waves in the human body in very low frequencies

In this paper we studied the effects of external fields' polarization on the coupling of pure magnetic fields into human body. Finite Difference Time Domain (FDTD) method is used to calculate the current densities induced in a 1 cm resolution anatomically based model with proper tissue conductivities. Twenty different tissues have been considered in this investigation and scaled FDTD technique is used to convert the results of computer code run in 15 MHz to low frequencies which are encountered in the vicinity of industrial induction heating and melting devices. It has been found that external magnetic field's orientation due to human body has a pronounced impact on the level of induced currents in different body tissues. This may potentially help developing protecting strategies to mitigate the situations in which workers are exposed to high levels of external magnetic radiation

Multi-scale modeling and mechanical performance characterization of stingray skeleton-inspired tessellations

This is the author accepted manuscript. The final version is available from the publisher via the DOI in this recordSharks and rays have distinctive skeletons among vertebrate animals, consisting primarily of unmineralized cartilage wrapped in a surface tessellation of minute polygonal tiles called tesserae, linked by unmineralized collagenous fibers. The discrete combination of hard and soft tissues is hypothesized to enhance the mechanical performance of tessellated cartilage (which performs many of the same functional roles as bone) by providing either rigidity or flexibility, depending on the nature of the applied load. These mechanisms and the effect of tesserae ultrastructure on cartilage mechanics, however, have never been demonstrated in the actual tissue, nor in bio-accurate models. Here, we develop bio-inspired three-dimensional tesserae computer models, incorporating material properties and ultrastructural features from natural tessellated cartilage. The geometries of ultrastructural features were varied parametrically, and the effective modulus of whole tesserae was evaluated using finite element analysis (FEA) to determine the roles of ultrastructural features in mechanics. Whereas altering some structural features had no effect on the macroscopic in-plane modulus of tesserae, a three-fold increase in the contact surface area between two adjacent tesserae increased the effective modulus of tesserae by 6%. Modeled stress distributions suggest that tesseral ‘spokes’ (distinct hypermineralized features in tesserae) bear maximum stresses in the skeleton and serve to funnel stresses to particular populations of cells in tesserae, while spokes’ lamellated structure likely helps dissipate crack energy, making tesserae more damage-tolerant. Simulations of multi-tesseral arrays showed that maximum stresses in tension and compression are borne by different tissues, supporting hypotheses of multi-functional properties of tessellated cartilage. Further, tesseral array models showed that minor alterations to tesserae/joint shape and/or material properties can be used to tune the mechanical behavior of the whole tiled composite. Our models provide the first functional understanding of the distinct morphologies of spokes and of ‘stellate’ tesserae (a tesseral shape observed first over 150 years ago), while also being useful drivers for hypotheses of growth, mechanics, load management, and the prevention and ‘directing’ of cracks in tessellated cartilage, as well as other biological composites. Additionally, these results establish guidelines and design principles for bio-inspired, tunable tiled materials

Genetic Characterization of Venezuelan Equine Encephalitis Virus from Bolivia, Ecuador and Peru: Identification of a New Subtype ID Lineage

Venezuelan equine encephalitis virus (VEEV) has been responsible for hundreds of thousands of human and equine cases of severe disease in the Americas. A passive surveillance study was conducted in Peru, Bolivia and Ecuador to determine the arboviral etiology of febrile illness. Patients with suspected viral-associated, acute, undifferentiated febrile illness of <7 days duration were enrolled in the study and blood samples were obtained from each patient and assayed by virus isolation. Demographic and clinical information from each patient was also obtained at the time of voluntary enrollment. In 2005–2007, cases of Venezuelan equine encephalitis (VEE) were diagnosed for the first time in residents of Bolivia; the patients did not report traveling, suggesting endemic circulation of VEEV in Bolivia. In 2001 and 2003, VEE cases were also identified in Ecuador. Since 1993, VEEV has been continuously isolated from patients in Loreto, Peru, and more recently (2005), in Madre de Dios, Peru. We performed phylogenetic analyses with VEEV from Bolivia, Ecuador and Peru and compared their relationships to strains from other parts of South America. We found that VEEV subtype ID Panama/Peru genotype is the predominant one circulating in Peru. We also demonstrated that VEEV subtype ID strains circulating in Ecuador belong to the Colombia/Venezuela genotype and VEEV from Madre de Dios, Peru and Cochabamba, Bolivia belong to a new ID genotype. In summary, we identified a new major lineage of enzootic VEEV subtype ID, information that could aid in the understanding of the emergence and evolution of VEEV in South America

Phenoloxidase activity acts as a mosquito innate immune response against infection with semliki forest virus

Several components of the mosquito immune system including the RNA interference (RNAi), JAK/STAT, Toll and IMD pathways have previously been implicated in controlling arbovirus infections. In contrast, the role of the phenoloxidase (PO) cascade in mosquito antiviral immunity is unknown. Here we show that conditioned medium from the Aedes albopictus-derived U4.4 cell line contains a functional PO cascade, which is activated by the bacterium Escherichia coli and the arbovirus Semliki Forest virus (SFV) (Togaviridae; Alphavirus). Production of recombinant SFV expressing the PO cascade inhibitor Egf1.0 blocked PO activity in U4.4 cell- conditioned medium, which resulted in enhanced spread of SFV. Infection of adult female Aedes aegypti by feeding mosquitoes a bloodmeal containing Egf1.0-expressing SFV increased virus replication and mosquito mortality. Collectively, these results suggest the PO cascade of mosquitoes plays an important role in immune defence against arboviruses

A meta-analytic review of stand-alone interventions to improve body image

Objective Numerous stand-alone interventions to improve body image have been developed. The present review used meta-analysis to estimate the effectiveness of such interventions, and to identify the specific change techniques that lead to improvement in body image. Methods The inclusion criteria were that (a) the intervention was stand-alone (i.e., solely focused on improving body image), (b) a control group was used, (c) participants were randomly assigned to conditions, and (d) at least one pretest and one posttest measure of body image was taken. Effect sizes were meta-analysed and moderator analyses were conducted. A taxonomy of 48 change techniques used in interventions targeted at body image was developed; all interventions were coded using this taxonomy. Results The literature search identified 62 tests of interventions (N = 3,846). Interventions produced a small-to-medium improvement in body image (d+ = 0.38), a small-to-medium reduction in beauty ideal internalisation (d+ = -0.37), and a large reduction in social comparison tendencies (d+ = -0.72). However, the effect size for body image was inflated by bias both within and across studies, and was reliable but of small magnitude once corrections for bias were applied. Effect sizes for the other outcomes were no longer reliable once corrections for bias were applied. Several features of the sample, intervention, and methodology moderated intervention effects. Twelve change techniques were associated with improvements in body image, and three techniques were contra-indicated. Conclusions The findings show that interventions engender only small improvements in body image, and underline the need for large-scale, high-quality trials in this area. The review identifies effective techniques that could be deployed in future interventions

Branch Mode Selection during Early Lung Development

Many organs of higher organisms, such as the vascular system, lung, kidney, pancreas, liver and glands, are heavily branched structures. The branching process during lung development has been studied in great detail and is remarkably stereotyped. The branched tree is generated by the sequential, non-random use of three geometrically simple modes of branching (domain branching, planar and orthogonal bifurcation). While many regulatory components and local interactions have been defined an integrated understanding of the regulatory network that controls the branching process is lacking. We have developed a deterministic, spatio-temporal differential-equation based model of the core signaling network that governs lung branching morphogenesis. The model focuses on the two key signaling factors that have been identified in experiments, fibroblast growth factor (FGF10) and sonic hedgehog (SHH) as well as the SHH receptor patched (Ptc). We show that the reported biochemical interactions give rise to a Schnakenberg-type Turing patterning mechanisms that allows us to reproduce experimental observations in wildtype and mutant mice. The kinetic parameters as well as the domain shape are based on experimental data where available. The developed model is robust to small absolute and large relative changes in the parameter values. At the same time there is a strong regulatory potential in that the switching between branching modes can be achieved by targeted changes in the parameter values. We note that the sequence of different branching events may also be the result of different growth speeds: fast growth triggers lateral branching while slow growth favours bifurcations in our model. We conclude that the FGF10-SHH-Ptc1 module is sufficient to generate pattern that correspond to the observed branching modesComment: Initially published at PLoS Comput Bio